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NPTEL – Chemistry – Principles of Organic Synthesis, , Lecture 21 Free-Radical Reactions I, 9.1 Principles, Free radicals may be defined as the species that contain one or more unpaired electrons., They are generally less stable and react in fraction of seconds with another species., , 9.1.1 Formation of Free Radicals, Three general methods are used for the generation of free radicals., , 9.1.1.1 Thermal Generation, Two types of compounds dissociate to give free-radicals at moderate temperature: (i), compounds that have an intrinsically weak bond such as dialkyl peroixides (DO-O = 155, KJ mol-1), and (ii) compounds that, on fragmentation, form strongly bonded products,, such as AIBN which releases N2., , O, , NC, , N, , heat, O, , O., , 2, , heat, N, , 2, , CN, , ., CN, , +, , N2, , 9.1.1.2 Photochemical Generation, Light can bring the fragmentation of a compound if the wavelength of the light is, correspond both to an energy greater than that of the bond to be cleaved, and to an, electronic excitation of the molecule concerned. This procedure is suitable for the, formation of alkoxy radicals from alkyl nitrite or hypochlorites., , RO, , N, , light, O, light, , RO Cl, , Joint initiative of IITs and IISc – Funded by MHRD, , RO. + NO ., RO. + Cl ., , Page 1 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , 9.1.2 Reactions of Free Radicals, Four types of reactions are possible with free-radicals., , 9.1.2.1 Abstraction, Free radicals proceed reactions with saturated organic molecules by abstracting an atom, from carbon. The selectivity of the free radicals towards C-H bonds of different types is, determined by bond dissociation energy and polar effects. The rate of the abstraction, process increases as bond dissociation energy decreases. For examples:, , Bond:, Bond Dissociation, Energy (KJmol-1), Reactivity Order::, , H CH3, , H CH2Me, , H CHMe2, , 426, , 401, , 385, , H CH3 <, , H CH2Me, , <, , H CHMe2, , H CMe3, 372, <, , H CMe3, , Allylic and benzylic C-H bonds are weaker than those of saturated systems and exhibit, greater reactivity and selectivity with free radicals., ., , Br ., HBr, , Joint initiative of IITs and IISc – Funded by MHRD, , ., , Page 3 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , Secondly, polar effect is also operative in radical reactions. For example, the relative, reactivity of C-H bonds in butyl chloride towards chlorine atom follows:, 6, , 1, Cl, , 1.5, 3, Number refers relative, electron density., , Chlorine atom is electronegative and preferentially reacts at C-H bonds of relatively high, electron density., In contrast, alkyl radicals which are called nucleophilic radicals react preferentially at CH bonds with electron density low., , 9.1.2.2 Addition, Free radicals undergo addition to carbon-carbon double bonds. The reaction is generally, selective. For example, addition to CH2=CHX takes place exclusively at the methyl, group, irrespective of the nature of X., ., , R, R., , X, , X, R, ., , X, , Alkynes also exhibit similar reactivity with free radicals., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 4 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , As we can see, in chlorination, both the propagating steps are exothermic reactions. Thus,, the chain reaction competes very effectively with the termination steps and the chains are, long., In contrast, in bromination, the first of the propagating steps is endothermic and its, activation energy is essentially at least as great as 62 kJ mol-1. Thus, the reaction is, slower than compared to chlorination. As a result, the terminating process competes with, the propagating step that leads to the chains short., In iodination, the reaction is strongly endothermic (129 kJ mol-1) that lead to ineffective., In the case of fluorination, both the propagating steps are exothermic that leads to violent, reaction with fragmentation of the alkyl groups. Thus, fluorination is usually carried out, by other methods., , 9.2.1.2 Applications, Radical-catalyzed chlorination and bromination of alkanes take place readily, both in gas, and liquid phases. Both the thermal and photochemical generation of the halogen atoms, are used., , Initiator, SO2Cl2 + R ., . SO Cl, 2, , R., RCl + . SO2Cl, SO2 + . Cl, , . Cl + RH, , HCl + . R, , . R + SO Cl, 2 2, , RCl + . SO2Cl, , propagation, , For example, cyclohexane reacts with sulfuryl chloride in the presence of dibenzoyl, peroxide to give cyclohexyl chloride in 89% yield., Cl, +, , SO2Cl2, , peroxide, , Joint initiative of IITs and IISc – Funded by MHRD, , + SO2, , + HCl, , Page 7 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , Similarly, the gas phase bromination of isobutane gives t-butyl bromide exclusively., Br2, H, , Br, , + HBr, , 9.2.2 Hunsdiecker Reaction, Treatment of aqueous solution of silver oxide with carboxylic acid gives silver salt of, carboxylic acid which reacts with Br2 to give a bromo-compound with elimination of, CO2., Ag2O, , CO2H, , Br, , Br2, , Mechanism, The reaction involves the formation of acyl hypobromite and its homolytic cleavage to, give acyloxy radical which loses CO2 and the resulting radical reacts with bromine, radical or abstracts bromine from a second molecule of the hypobromite., , Ag2O + H2O, O-H, , AgOH +, OH, , O, , O, , HO, , + Ag, O Br, , Br-Br, , O Ag -AgBr, , Ag, , O., , -Br., O, , O, O Br, , Br ., , Br, , or, , ., , O, , O., , Br +, O, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 8 of 22, , .

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NPTEL – Chemistry – Principles of Organic Synthesis, , Problems:, A. How would you employ radical reactions in the synthesis of the following compounds?, Br, Br, , 1., , 2., , MeO, 3., , 4., , Br, Cl, , Br, , B. Complete the following reactions., , 1., , Ph, , Ag, , Cl, , Ph Ph, , NOCl, , 2., , light, Me, , Bu3SnH, , 3., Br, , 4. Ph, , 5. PhCHO, , light, BrCCl3, light, Bu3SnH/AIBN, +, , CO2Me, , Text Books:, R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New, York, 2009., J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 10 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , The following are some examples for radical addition to carbon-carbon double bond with, a variety of types of starting material., O, , O, , peroxide, , H +, , O, , O, peroxide, +, , peroxide, +, , OH, , OH, peroxide, , OH, , +, , OH, , N, H, , N, H, , 9.3.2 The Coupling of Alkynes, Copper(II) complex catalyzes the coupling of acetylene and monosubstituted acetylenes, to yield diynes in the presence of base such as pyridine. The reaction probably takes place, via one-electron oxidation of the acetylide anion by copper(II) ion followed by, dimerization of the resulting acetylide radicals:, , Base, R, , H, , R, , Cu(II), , R, , . + Cu(I), dimerization, , R, , Joint initiative of IITs and IISc – Funded by MHRD, , R, , Page 12 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , Alternative method has also been developed using an aqueous mixture of copper(I), chloride and ammonium chloride under air. Under these conditions, removal of the, proton may be facilitated by complexing between the carbon-carbon triple bond and, copper(I) ion., , R, , H, , + H, , R, , Cu(I), , Cu(I), , Since the reaction functions under air, some of the Cu(I) could be oxidized to Cu(II), which in turn could oxidize the acetylide ion to the acetylide radical that could dimerize, to yield diynes. The following are examples of many synthetic applications., , The, , synthesis of phellogenic acid has been accomplished from undecylenic acid:, , CO2H, Cu(I), O2, , HO2C, , HO2C, , H2, Pd, , HO2C, , CO2H, Phellogenic acid, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 13 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , In some cases, intramolecular coupling of terminal alkynes may also occur to produce, cyclic compounds, if the resulting ring is not highly strained. For example, the synthesis, of macrocyclic lactone, exaltolide, that is partly responsible for the sweet odour of the, angelica root, could accomplished with high yield., , O, OH, , +, , Cl, , O, O, , O, Cu(I), O2, , O, , -HCl, , O, , H2, Pt, , O, , exaltolide, , Coupling of monosubstituted acetylene with 1-bromoalkyene can be performed to afford, hetero coupled product in good yield., , HO, , +, , Br, , Me, , Cu(I), , Me, , -HBr, , HO, , Dehydromatricarianol, , 9.3.4 Acyloin Condensation, Aliphatic ester reacts with molten sodium in hot xylene to yield the disodium derivative, of acyloin which is converted into acyloin in the presence of acid. The reaction is to be, carried out under nitrogen because acyloins and their anions are prone to undergo, oxidation with air., , O, R, , O, , Na/xylene, , OH, , R, , OR', H, , Joint initiative of IITs and IISc – Funded by MHRD, , R, , Page 14 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , Mechanism, The reaction is initiated by electron transfer from sodium to the carbonyl group of the, ester. The resulting radicals dimerize and the alkoxides are eliminated. The diketone, further reacts with sodium to give disodium derivative which reacts with acid to give, acyloin., , Na ., O Na, , O, e, R, , OR', , R . OR', , O Na, R, ., R, ., O Na, , 2Na., , O Na, R, , O, , O Na, , dimerization Na O, R, R'O, , -2NaOR' R, , R, OR', , R, O, , O, , OH, 2H, , R, , R, , R, O Na, , R, , R, OH, , OH, , The alkoxide generated during the reaction can catalyze condensation of the ester. To, prevent this competitive reaction, the alkoxides are trapped using chlorotrimethylsilane, and the acyloin is then released with acid. This procedure gives better results compared to, the traditional Dieckmann cyclization for preparation of larger rings., , Me3SiCl + NaOR', , Me3SiOR' + NaCl, OSiMe3, , O Na, R, , R, O Na, , 2Me3SiCl, 2NaCl, , R, , R, OSiMe3, , O, , OH, H3O, , Joint initiative of IITs and IISc – Funded by MHRD, , R, , R, , R, , R, OH, , OH, , Page 15 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , For example, the synthesis of aldosterone 21-acetate from corticosterone acetate has been, demonstrated., , HON, , O, , Me, , HO, Me, , OAc, , OAc, , OAc, , O, O, HNO2 HO, Me, , HO, Me, , NOCl, , OAc, , OH, , O, , O, , O, Me, , light, O, , O, , O, , O, , Mechanism, Photolysis of organic nitrites gives oxy-radical which abstracts hydrogen from a δ-CH, bond. The resulting alkyl radical reacts with nitric oxide liberated during the photolysis to, yield a nitroso-derivative which tautomerizes to oxime that can be hydrolyzed to carbonyl, group., , R  H, , , R, , OH, , , NOCl, , H, , O, , NO, , , , H, , R, , H, , OH, N, , R, , OH, , H, , R, light, -NO., , H, , OH, N, , OH, , H2O, , R ., , O., , R, H2O, , H, , OH, , NO., , R, , OH, N, , OH, , R, H-O, , O, N, , OH, , H OH, N, OH, H, , OH, N, OH, , R, , -NH2OH, , R, , OH, OH, , R, , O, , -H, OH, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 17 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , 9.4.2 Barton Decarboxylation, Thiohydroxamate ester (commonly referred to as a Barton ester) with tributytin hydride, or t-butylmercaptan in the presence of a radical initiator undergoes decarboxylation to, give alkanes. The driving for this reaction is the S-Sn bond formation., , O, +, , X, , N, S, O Na, , AIBN, Bu3SnH, R, , R-H, , heat, , Mechanism, Instead of direct reaction of oxygen with the acid chloride, the following occurs:, O, Cl, , R, , .., N, S, O Na, , N, O, , S, , O, , -X, , X O, , N, O, , R, , S, , N, O, , R, , S, O, R, , N, O, , R, O, , Decarboxylation, NC, , CN, N N, CN, ., , CN, 2 ., , heat or, light, , + N2, , CN, , H-Sn(n-Bu)3, , H, , + . Sn(n-Bu)3, , Decarboyxlation Step, , N, O, , R, , S, , . Sn(n-Bu), , O, CO2 + R ., , O, 3, , N, , S + R, Sn(n-Bu)3, , H-Sn(n-Bu)3, , Joint initiative of IITs and IISc – Funded by MHRD, , R-H, , O., , + . Sn(n-Bu)3, , Page 18 of 22, , S

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NPTEL – Chemistry – Principles of Organic Synthesis, , Examples:, O, , S, , O, N, , NHBoc, H, N, , t-BuSH, , R, , light, , Boc, , R 78%, , D. H. R. Barton, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1988, 44, 5479., Me, Barton Me, , S, , Cl +, EtO2C, , O, , N, OH, , N, , CO2Et, , S, , E. Bacque, F. Pautrat, S. Z. Zand, Org. Lett. 2003, 5, 325., , 9.5 Formation of Carbon-Oxygen Bonds, In a wide variety of environments, C-H bond undergoes oxidation on standing in air to, give hydroperoxides. For example, ethers proceed autoxidation to give -hydroperoxide., , O2, O, , O2H, , O, , Since hydroperoxides are known to explode on heating, it is essential to remove them, (e.g. by reduction with aqueous iron(II) sulfate) from ethers before their use as solvents, for the reactions., Isobutane can be transformed into t-butyl hydroperoxide in the presence of initiator., , Me, Me, Me, , O2, , H, , Joint initiative of IITs and IISc – Funded by MHRD, , Me, Me, Me, , OOH, , Page 19 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , Alkenes are more reactive compared to alkanes due to greater stability of allyl radicals, compared to alkyl radicals., , O2H, O2, , 9.6 Formation of Bonds to Other Elements, Elements such as sulfur, phosphorus and silicon can proceed reactions with alkenes and, alkynes via radical catalyzed process. The characteristics of these reactions are similar to, those described above. For example,, , Cl3SiH +, PH3 + 3, , SH +, , Joint initiative of IITs and IISc – Funded by MHRD, , SiCl3, P, 3, , S, , Page 20 of 22

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NPTEL – Chemistry – Principles of Organic Synthesis, , Text Books:, R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New, York, 2009., J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 22 of 22